ONIOM and FMO-EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site / Paweł Śliwa, Rafał Kurczab, Andrzej J. Bojarski // International Journal of Quantum ... więcej

ONIOM and FMO-EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site / Paweł Śliwa, Rafał Kurczab, Andrzej J. Bojarski // International Journal of Quantum Chemistry [Dokument elektroniczny]. – 2018, Vol. 118, Iss. 15, 12 s. : rys., wykr. – Tryb dostępu: http://onlinelibrary.wiley.com/doi/10.1002/qua.25617/epdf. – Bibliogr. 96 poz., Abstr. – Data udostępnienia online: 2018-03-01. – doi: 10.1002/qua.25617. – ISSN 1097-461X

The crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazol-2-yl)-N-methylbenzamide (FITM, a negative allostericmodulator) ... więcej

The crystal structure of metabotropic glutamate receptor 1 (mGluR1) complexed with 4-fluoro-N-(4-(6-(isopropylamino)pyrimidin-4-yl)thiazol-2-yl)-N-methylbenzamide (FITM, a negative allostericmodulator) and its twelve close structural analogs with a broad spectrum of affinities (2.4nM < IC50> 10 000 nM) were investigated using quantum mechanical methods. The our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) was used to optimize themolecular geometries of the receptor with complexed ligands, which were then used to performthe ab initio calculations using the fragment molecular orbitals method with energy decompositionanalysis (FMO-EDA). The results clearly showed that residues Q6603.28and/or Y8056.55were theanchoring points for all the studied analogs of FITM, while the H-bond with T8157.38determinedonly the orientation of very active molecules containing an amino substituent in the pyrimidinemoiety (e.g., FITM). The orientation of the other parts of ligands resulted from hydrophobic inter-actions mainly with L7575.44,F8016.51,orW7986.48.TheappliedONIOM/FMO–EDA approachfacilitated the study of effects related to very small changes in the ligand structure and led to con-clusions regarding the significance of individual interactions in the allosteric binding pocket ofmGluR1.